(19) TZZ _T (11) EP 2 756 756 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 23.07.2014 Bulletin 2014/30 A01N 43/42 (2006.01) A61K 31/44 (2006.01) (21) Application number: 14165112.5 (22) Date of filing: 24.04.2009 (84) Designated Contracting States: • Turanin, John AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Emeryville, CA California 94608 (US) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • Hawley, Roger PT RO SE SI SK TR Emeryville, CA California 94608 (US) • Schuster, Jeffrey, A. (30) Priority: 28.04.2008 US 48463 Bolinas, CA California 94924 (US) (62) Document number(s) of the earlier application(s) in (74) Representative: Duxbury, Stephen et al accordance with Art. 76 EPC: Arnold & Siedsma 09739139.5 / 2 273 880 Pettenkoferstrasse 37 80336 München (DE) (71) Applicant: Zogenix, Inc. Emeryville CA 94608 (US) Remarks: This application was filed on 17-04-2014 as a (72) Inventors: divisional application to the application mentioned • Farr, Stephen J. under INID code 62. Orinda, CA California 94563 (US) (54) Novel formulations for treatment of migraine (57) Systems and methods are described for treating Systems that are self contained, portable, prefilled, and un-met medical needs in migraine and related conditions simple to self administer at the onset of a migraine attack such as cluster headache. Included are treatments that are disclosed, and preferably include a needle-free in- are both rapid onset and long acting, which include sus- jector and a high viscosity formulation, to eliminate such tained release formulations, and combination products, issues as fear of self administration with needles, and Also included are treatments for multiple symptoms of needle stick and cross contamination. migraine, especially headache and nausea and vomiting. EP 2 756 756 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 756 756 A1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to novel formulations for treatment of migraine and cluster headache. Various classes of formulations including novel combinations and sustained release formulations are listed. Preferably these formulations are applicable to needle-free delivery. BACKGROUND OF THE INVENTION 10 [0002] Migraine is a debilitating neurological disease that causes numerous acute symptoms, including headache, nausea, vomiting, and a heightened sensitivity to bright lights and noise. Untreated, attacks last from several hours to a few days. Approximately 1/3 of suffers experience aura, the perception of strange light or smell at the onset of an attack. [0003] Susceptibility to migraine is widespread, with 18% of women and 6% of men report having had at least one 15 migraine episode in the previous year [Lancet 2004;363:381-391], and it will affect 12-28% of people during their lifetimes. [Eur J Neurol 2006;13:333-45]. The highest rates are found in women, between puberty and menopause. Studies in twins have shown a genetic component of migraine susceptibility, and it is twice as prevalent in the families of epilepsy sufferers [Ottman, R and Lipton, R, Neurology, 1994]. Migraine’s annual direct medical costs exceed $1 billion, and the yearly cost to employers is approximately $13 billion. 20 [0004] Many drug and non-drug treatments are used for migraine. Non drug treatments include cold or hot shower, resting in a dark, silent room, coffee, massage or physical therapy, acupuncture, acupressure, biofeedback, self-hypnosis, herbal remedies, and diet. Recent data have suggested a possible correlation between patent foramen ovale (PFO) and migraine with aura (Headache, Oct 2007), and studies are underway to determine if surgically closing PFO has any impact on migraine. 25 [0005] Preventative drug treatments that have been used include low dose aspirin, beta blockers, antihistamines (including pizotifen) anticonvulsants (including divalproex), monoamine oxidase inhibitors (MAOIs, including phehelzine, isocarboxazid), antidepressants for example tricyclic antidepressants (TCAs, including amitriptyline, nortriptyline, dox- epin, and protriptyline) selective serotonin reuptake inhibitors (SSRIs), methysergide (although it has been withdrawn from the US market due to side effects), and memantine. Beta blockers include but are not limited to non-selective 30 agents (Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol , Oxprenolol, Penbutolol, Pindolol, Pro- pranolol, Sotalol, Timolol) β1-Selective agents (Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebiv- olol) Mixed α1/β-adrenergic antagonists (Carvedilol, Celiprolol, Labetalol) andβ2-Selective agents (Butaxamine). WO0219213A2 discloses use of PDE-5 inhibitors for treatment of prevention of migraine, including an example where a human migraine suffer is migraine free for 18 months while taking sildenafil citrate 3 or 4 times weekly, wherein the 35 migraines returned when the treatment was ceased. Zonisamide has been studied for and used as a migraine preventative medication [0006] Many acute, abortive treatments are used in the treatment of migraine. Selective serotonin receptor agonists known as "triptans" are widely prescribed, and include sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, donitriptan and zomitriptan. Different triptans have varying pharmacokinetic parameters. Sumatriptan has a 40 half life of 2.5 hours, rizatriptan has a half life of 2-3 hours, naratriptan has a half life of 5-8 hours, zolmitriptan has a half life of 3 hours, eletriptan has a half life of 4 hours, almotriptan has a half life of 3-4 hours, and frovatriptan has a half l ife of 26 hours. [0007] Prior to the introduction of triptans and 1991, ergopeptines, including ergotamine, methysergide, and dihydro- ergotamine were the standard of care for oral drugs. NSAIDs including aspirin, ibuprofen, naproxen, and acetaminophen 45 are available over the counter, while other NSAIDS including diclofenac, flurbiprofen, meclofenamate, isometheptene and indomethacin are available by prescription. Opioid analgesics include codeine, morphine, hydrocodone, acetyldi- hydrocodeine, oxycodone, oxymorphone, papaverine, fentanyl, alfentanil, sufentanil, remifentanyl, and tramadol. Phe- nothiazines, including prochlorperazine, have been used to treat nausea and vertigo, and are being developed to treat migraine pain. Cox-2 inhibitors include celecoxib (Celebrex®), rofecoxib (Vioxx®), meloxicam, piroxicam, JTE-522 (Japan 50 Tobacco, inc.), L-745,337, NS398, deracoxib, valdecoxib, Iumiracoxib, etoricoxib, parecoxib, 4- (4- cyclohexyl-2-meth- yloxazol-5-yl)-2 fluorobenzenesulfonamide, 2-(3,5- difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2 cyclopenten-1 -one, N- [2- (cyclohexyloxy)-4-nitrophenyl]methanesulfonamide, 2-(3,4 difluorophenyl)- 4-(3-hydroxy-3-methylbutoxy)- 5-[4-(methylsulfonyl) phenyl]-3(2H) pyridazinone, 2-[(2,4-dichloro-6-methylphenyl) amino]-5-ethyl- benzeneacetic acid, (3Z) 3-[(4-chlorophenyl) [4-(methylsulfonyl)phenyl] methylene]dihydro-2(3H)- furanone, and (S)-6,8-dichloro-2-(trifluor- 55 omethyl) -2H-1-benzopyran-3- carboxylic acid. Barbiturates can be used, including amobarbital, butalbital, cyclobarbital, pentobarbital, allobarbital, methylphenobarbital, phenobarbital, secobarbital, and vinylbital. Ion channel modulators, particularly calcium channel blockers (Verapamil, Diltiazem, Nifedipine) or sodium or potassium channel modulators, may be useful in the treatment of migraine. EP0754453B1 discloses the topical use of local anesthetics, including 2 EP 2 756 756 A1 lidocaine, tetracaine, prilocaine, bupivicaine, mepivacaine, etidocaine, procaine and benzocaine. Monoamine oxidase inhibitors (MAOIs) may be used, including phehelzine and isocarboxazid. Other useful drugs include dichloralphenazone, nimopidine, substance P antagonists, capsaicin receptor agonists, botulinum toxin, captopril, tiospirone, or steroids. For any of these compounds variants including but not limited to an isomer, a pharmaceutically acceptable salt, ester, or 5 prodrug thereof also may be used. [0008] Combinations products have been used, including combinations of aspirin, acetaminophen, and caffeine (Exe- drin™, Novartis), caffeine and ergotamine (Migerot ™, G and W Labs), butalbital, acetaminophen and caffeine (Fioricet ™, Watson Pharmaceuticals, also available in combination with Codeine, and Esgic ™, Mikart), butalbital, aspirin and caffeine (Fiorinal™, Watson Pharmaceuticals, also available in combination with Codeine). Research has shown that a combi- 10 nation of sumatriptan and naproxen was more efficacious than either drug alone [JAMA 297 (13): 1443-54]. US6586458 describes a combination of a 5-HT agonist with a long acting NSAID. WO0215899A1 discloses compositions comprising a selective 5-HT receptor agonist and acetaminophen, non-steroidal anti-inflammatory agents and/or caffeine. WO0048583A2 discloses combinations of 5-HT agonists and COX-2 inhibitors. US5597826 discloses combinations of Sertraline and 5-HT agonists for the treatment of migraine or cluster headache. WO0021536A1 discloses use of LEU- 15 KOTRIENE LTD4 RECEPTOR BLOCKER DRUGS, possibly in combination with Triptans, for the treatment of migraine and cluster headaches. EP1056448B1 discloses combinations of Tramadol and metoclopramide or domperidone. WO07103113A2 discloses combinations of opioids and NSAIDs. US20030133951A1 discloses nicotine receptor partial agonist and an analgesic agent. Midrin is a combination of acetaminophen, dichloralphenazone, and isometheptene used mostly to treat headaches (also